Core Refinement toward Permeable 尾-Secretase (BACE-1) Inhibitors with Low hERG Activity
详细信息 查看全文
- 作者：Tobias Ginman ; Jenny Viklund ; Jonas Malmstr枚m ; Jan Blid ; Rikard Emond ; Rickard Forsblom ; Anh Johansson ; Annika Kers ; Fredrik Lake ; Fernando Sehgelmeble ; Karin J. Sterky ; Margareta Bergh ; Anders Lindgren ; Patrik Johansson ; Fredrik Jeppsson ; Johanna F盲lting ; Ylva Gravenfors ; Fredrik Rahm
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：June 13, 2013
- 年：2013
- 卷：56
- 期：11
- 页码：4181-4205
- 全文大小：962K
- 年卷期：v.56,no.11(June 13, 2013)
- ISSN：1520-4804
文摘
By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer鈥檚 disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure鈥揳ctivity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 渭M to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.